Following recognition by antibody and complement activation, C3b and C4b fragments accumulate on foreign targets. Autologous cells can also be attacked by complement, for example when recognized by autoantibodies. Moreover, the alternative and classical complement pathways are probably constantly turning over under physiological conditions. Whenever nascent C3b is generated, it is likely that some molecules can bind to autologous cells in the proximity. Until a few years ago the mechanisms of control of the C3b or C4b bound to autologous cells were obscure. Recent evidence from several laboratories indicates that the activities of these complement fragments are inhibited by specific membrane molecules. Two of them have been identified, the complement receptor type 1 (CR1) and the decay-accelerating factor (DAF). There is also growing suspicion that there are additional control proteins on the surfaces of mammalian cells, designed to inhibit the function of components of the membrane attack complex. Our long term objective is to study the structure and function of the components of this new family of complement inhibitors, and to devise methods to modulate their activity within the cell membrane. Our specific aims are: A) To clarify the mechanisms of control of the activities of C3b and C4b bound to autologous cells. B) To study the structure and function of DAF and of the DAF variants found in extracellular fluids and cell membranes. C) To study the nature of the molecular defect which leads to the DAF deficiency observed in patients with paroxysmal nocturnal hemoglobinuria (PNH). If the membrane control proteins are identified, and their functional properties are known, we should be able to influence, and perhaps control, the outcome of the "in vitro" attack by complement. Interesting applications can be foreseen, such as the destruction of selected populations of cells from samples of bone marrow preceding their transplantation into a patient.